Novel cyclosporine preparation forms for oral administration of simple composition and high bio-availability, and process for producing them

ABSTRACT

The invention relates to formulations of cyclosporin with high bioavailability for oral administration, which contain about 1 part by weight of one or more cyclosporin(s), preferably cyclosporin A and/or cyclosporin G, 7.5 to 7.8 parts by weight of one or more polyethylene glycol esters of saturated C 10 -C 22  hydroxy fatty acids, 0.7 to 0.85 part by weight of a monohydric alcohol as co-solvent, and 0.7 to 0.8 part by weight of a polyhydric alcohol as co-solvent. The drug form is produced by initially dissolving the cyclosporin in ethanol and, while stirring, adding propylene glycol and SOLUTOL® HS 15 until a clear, viscous solution results, bottled as drinkable solution or packed into capsules.

CROSS-REFERENCE

[0001] This is a continuation of Ser. No. 09/605,512, Jun. 6, 2000,pending, which is a continuation of Ser. No. 09/134,298, Aug. 14, 1998,abandoned, which is a continuation of Ser. No. 08/806,106, Feb. 25,1997, abandoned, which is a CIP of PCT/DE95/00951, Jul. 19, 1995.

BACKGROUND OF THE INVENTION

[0002] The invention relates to cyclosporin, especially cyclosporin A,containing liquid formulations and soft gelatin capsules for oraladministration.

[0003] Cyclosporins are neutral cyclic peptides produced by microbes.The most important representative of the cyclosporins is cyclosporin A,which is used in transplant therapy for suppressing organ rejection andin bone marrow transplantation.

[0004] Cyclosporin A, its microbiological production, and its isolationand purification to an amorphous, colorless powder is disclosed per sein German Patent 2,455,859.

[0005] Cyclosporin A is increasingly also being used in the treatment ofautoimmune diseases such as psoriasis, uveitis, nephrotic syndrome andothers.

[0006] Antiinflammatory and antiparasitic properties are described forthe cyclosporins.

[0007] Because of the hydrophobic nature of cyclosporin, it is difficultto produce pharmaceutical compositions resulting in high bioavailabilityof the active ingredient, and there is a very wide inter- andintra-individual variability in the pharmacokinetic parameters. At thesame dose, the cyclosporin level in the blood varies by up to 50% frompatient to patient. Absorption varies widely even in one and the samepatient. However, immunosuppressive therapy relies on a very narrowtherapeutic window between dose-dependent side effects and rejection ofthe transplanted organ.

[0008] Poor bioavailabilities are attributable in particular to the lowsolubility of cyclosporin in the mixture of cyclosporins in dosage formscontaining water.

[0009] There have thus been very numerous attempts to solve thesepharmaceutical problems.

[0010] Known and commercially available dosage forms accordingly employcomplicated systems of lipophilic and hydrophilic solvents andsolubilizing detergents, with the aim of dissolving cyclosporins andkeeping them in solution in aqueous systems. They consist of at leastfour ingredients: namely, active ingredient, vege-table oil, ethanol,and a surfactant.

[0011] U.S. Pat. No. 4,388,307 discloses the use of oil and ethanol asvehicle in conjunction with co-solvents. Based on this patent,commercially available drinkable solutions of cyclosporin contain oliveoil, ethanol and, as surface-active substance, Labrafil®. This formulaentails problems, however. Oils and surface-active vehicles often havean unpleasant odor and/or taste. In addition, oils with unsaturatedfatty acids are prone to rancidity.

[0012] Secondly, a relatively high content of ethanol is necessary informulas containing oils. However, this high ethanol content entailsdifficulties on administration of the products to children and resultsin storage problems.

[0013] When used for filling capsules it is necessary, for the purposeof preventing evaporation, to increase the elaboration of finishing bypackaging in aluminum blister packs.

[0014] Newer dosage forms disclosed in GB Patent 2,222,770 compriseroutes to solutions by the production of micro-emulsions. These systemsconsist of 4 to 6 components which form a complicated system of activeingredient, lipophilic, hydrophilic phase, and a surface-activesubstance. Systems of this type entail an increased risk ofcross-reaction and the risk that one of the substances used is nottolerated by the patient.

[0015] German Patent 3,924,207 discloses a process for producing stableaqueous injection solutions for intravenous administration, which can beadministered orally, in which

[0016] a) 1 part by weight of cyclosporin

[0017] b) 8-13 parts by weight of one or more monoesters of a or ofsaturated hydroxy fatty acids with polyethylene glycol and

[0018] c) 1-13 parts by weight of one or more mono- and/or polyhydricalcohols are mixed.

[0019] Pharmaceutical forms which can be used orally have not beenproduced and investigated in this patent. On attempting to produceformulations in the lower concentration ranges, stated by the inventors,of one or more mono- or polyhydric alcohols, no solution which canprovide clear dilutions with water, which is essential for goodbioavailability of the active ingredient, is obtained.

[0020] All commercially obtainable dosage forms contain oily, lipophilicingredients (corn oil, kernel oil, corn oil mono-, di-, triglycerides)and one or more detergents and mono- or polyhydric alcohols.

[0021] It is evident from DE-A 3,843,054 that orthorhombic crystallineforms such as CY-A/X-II and, in particular, CY-A/X-III are particularlysuitable for producing pharmaceutical forms. These formulations are saidto contain cyclosporin in stable and fine-particle form and/or havebetter stability or more favorable release characteristics. These formsare preferably for topical dermal or topical ophthalmic use. The processdescribed for producing the solvate-free orthorhombic crystal formsusing ultrasound is difficult to implement on the industrial scale.

[0022] It is likewise shown that cyclosporin in amorphous form is lesssuitable for producing dosage forms.

SUMMARY OF THE INVENTION

[0023] The problems which have been described have been solved accordingto the invention by the surprising finding that in cyclosporin dosageforms for oral administration with a simple composition and highbioavailability in the form of drinkable solution or capsulescontaining:

[0024] a) 1.0 part by weight of one or more amorphous cyclosporin(s) asactive ingredient;

[0025] b) 7.5 to 7.8, preferably 7.7, parts by weight of one or morepolyethylene glycol monoesters of saturated C₁₀ to C₂₂ hydroxy fattyacids, preferably SOLUTOL® HS 15;

[0026] c) 0.7 to 0.85, preferably 0.75, part by weight of a monohydricalcohol as co-solvent, preferably ethanol; and

[0027] d) 0.7 to 0.8, preferably 0.75, part by weight of a polyhydricalcohol as co-solvent, preferably propylene glycol the cyclosporin(s)provide clear solutions, especially in dilutions with water, when thesespecific ratios of amounts are maintained.

DETAILED DESCRIPTION OF THE INVENTION

[0028] With the selection of this specific solvent composition of aplurality of mono- and polyhydric alcohols in conjunction with the useof amorphous cyclosporin, a formulation which can provide cleardilutions with water in all ratios, especially at high concentrations ofcyclosporin in the dosage form, has been found.

[0029] This was not normally to be assumed because the concentrations ofthe co-solvent stated in German Patent 3,924,207 does not permit stableaqueous solutions to be produced in the lower concentration range. Onlythe combination of mono- and polyhydric alcohols in the stated ratiomakes it possible to produce solutions which have a high cyclosporincontent and which afford solutions which can provide clear dilutionswith water. It is furthermore essential for the possibility of providingclear dilutions with water that the ratio of the monohydric alcohol tothe polyethylene glycol monoester is maintained and that the formulacontains both mono- and polyhydric alcohols.

[0030] It was, therefore, all the more surprising that such a formulashowed a bioequivalence with commercial products (see above).

[0031] In particular, it was not predictable that such a simple formulawithout lipophilic component could achieve such high bioavailabilities.

[0032] It has furthermore been found that precisely the use of amorphouscyclosporin in an oral administration form results in particularly goodsolution properties in formulas with a cyclosporin content>5%, which arealso maintained in dilutions with water as stable, clear solution.

[0033] The invention, therefore, relates to oral dosage forms which, asdrinkable solution or packed in capsules, contain the followingingredients in the following ratios of amounts:

[0034] a) 1.0 part by weight of one or more amorphous cyclosporin(s) asactive ingredient;

[0035] b) 7.5 to 7.8, preferably 7.7, parts by weight of one or morepolyethylene glycol monoesters of saturated C₁₀ to C₂₂ hydroxy fattyacids, preferably SOLUTOL® HS 15;

[0036] c) 0.7 to 0.85, preferably 0.75, part by weight of a monohydricalcohol as co-solvent, preferably ethanol; and

[0037] d) 0.7 to 0.8, preferably 0.75, part by weight of a polyhydricalcohol as co-solvent, preferably propylene glycol.

[0038] In the production process, which is likewise according to theinvention, care must be taken that the ratios of amounts are maintainedand that the cyclosporin is initially completely dissolved in ethanolwith continuous stirring at room temperature and subsequently, likewisewith continuous stirring and at room temperature, propylene glycol andSolutol® HS 15 are added. The solutions produced by this process contain100 mg/mL active ingredient.

[0039] Finishing as drinkable solution or capsules takes place in aknown manner, for example in capsules each containing 190 mg, 50 mg, or25 mg of active ingredient.

[0040] The production of the composition according to the invention isexplained in detail in the following examples:

EXAMPLE 1

[0041] 100 g of amorphous cyclosporin A are dissolved in 95 mL ofethanol with stirring at room temperature. Subsequently, while stirringfurther at room temperature, 72 mL of propylene glycol are added. Aftera clear solution of cyclosporin A has been obtained, 770 g of Solutol®HS 15 are added with further stirring. A clear, viscous solutioncontaining 100 mg/mL cyclosporin A results.

EXAMPLE 2

[0042] A cyclosporin A solution produced as in Example 1 is diluted inthe ratio 1:40 with water. The resulting solution remains clear andstable over several months.

EXAMPLE 3 Drinkable Solution A

[0043] Formula

[0044] cyclosporin A, 5.00 g

[0045] ethanol 96%, 3.75 g

[0046] propylene glycol 3.75 g

[0047] Solutol® HS 15 ad 50.0 mL=38.39 g.

[0048] Production takes place by dissolving the cyclosporin in theethanol, adding propylene glycol, inducing and adding {fraction (2/3)}of the molten Solutol® and homogenizing. The volume is subsequently madeup to 50.0 mL with Solutol®, and homogenization is repeated.

EXAMPLE 4 Drinkable Solution B

[0049] Formula

[0050] cyclosporin A, 10.0 g

[0051] propylene glycol 7.5 g

[0052] Solutol® HS 15 77.0 g

[0053] ethanol 96% ad 100 mL=8.18 g

[0054] Production:

[0055] 10.0 g of cyclosporin are dissolved in 5 g of ethanol and 7.5 gof propylene glycol, and 77.0 g of Solutol® in the molten state areadded. The solution is homogenized and equilibrated at about 25° C. Thevolume is subsequently made up to 100 mL with ethanol and homogenizationis repeated.

EXAMPLE 5

[0056] The formulations obtained in accordance with Examples 3 and 4were tested for bioavailability in beagle dogs compared with products Iand II available on the market.

[0057] Beagle dogs are regarded as a predictive model for humans for thepharmacokinetics and bioavailability of cyclosporins (compare Ritschelet al., Meth. and Find. Exp. Clin. Pharmakol. 1989, 11(4):281-287).

[0058] The results demonstrate a comparable or better relativebioavailability of the drinkable solutions A and B according to theinvention compared with comparative products I and II, while theproduction is considerably simpler.

BRIEF DESCRIPTION OF THE DRAWING

[0059] The relative bioavailability (area under the plasmaconcentration-time curves) of drinkable solutions A and B is depicted inFIG. 1 compared with the commercially available comparative products I(reference value=100%) and II.

What is claimed is
 1. Novel formulations of cyclosporin for oraladministration with high bioavailability in the form of a drinkablesolution or capsules containing: a) 1.0 part by weight of one or moreamorphous cyclosporins; b) 7.5 to 7.8, preferably 7.7, parts by weightof one or more polyethylene glycol monoesters of saturated C₁₀ to C₂₂hydroxy fatty acids, preferably SOLUTOL®HS 15; c) 0.7 to 0.8, preferably0.75, part by weight of a monohydric alcohol as co-solvent, preferablyethanol; and d) 0.7 to 0.8, preferably 0.75, part by weight of apolyhydric alcohol as co-solvent, preferably propylene glycol.
 2. Aformulation of claim 1 in unit dosage form comprising cyclosporin Aand/or cyclosporin G in amorphous form.
 3. A process for the productionof the novel formulations of claim 1, in which, initially while stirringat room temperature, a) 10 g of amorphous cyclosporin, especiallycyclosporin A, are dissolved in 7.0-8.5 g of ethanol; b) likewise whilestirring and at room temperature, 7.0-8.0 g of propylene glycol areadded; and c) finally, likewise while stirring at room temperature,75-78 g of Solutol® HS 15 are added, resulting in a clear, viscoussolution of the cyclosporin, which is made up to 100 mL with ethanoland, in a manner known per se, bottled as adrinkable solution or packedinto capsules.
 4. A formulation comprising: a) about 1 part by weightcyclosporin; b) 7.5 to 7.8 parts by weight of a polyethylene glycolmonoester of a saturated C₁₀-C₂₂ hydroxy fatty acid; c) 0.7 to 0.85 partby weight of a monohydric alcohol as co-solvent; and d) 0.7 to 0.8 partby weight of a polyhydric alcohol as co-solvent.
 5. A formulation ofclaim 4 comprising: a) about 1 part by weight cyclosporin; b) 7.7 partsby weight SOLUTOL® HS 15; c) 0.75 part by weight ethanol; and d) 0.75part by weight propylene glycol.
 6. A formulation of claim 4 wherein thecyclosporin is amorphous cyclosporin A or amorphous cyclosporin G.
 7. Aformulation of claim 4 further comprising water.
 8. A formulation ofclaim 4 further comprising water in the ratio cyclosporin to water offrom 1 to about
 40. 9. A process for the production a clear cyclosporinsolution comprising: a) dissolving about 1 part by weight cyclosporin infrom 0.7 to 0.85 part by weight of a monohydric alcohol as co-solventwith continuous stirring at room temperature; and b) adding from 0.7 to0.8 part by weight of a polyhydric alcohol as co-solvent and from 7.5 to7.8 parts by weight of a polyethylene glycol monoester of saturatedC₁₀-C₂₂ hydroxy fatty acid with continuous stirring at room temperature.10. A process of claim 9 wherein the cyclosporin is cyclosporin A.
 11. Aprocess of claim 9 wherein the monhydric alcohol is ethanol and thepolyhydric alcohol is propylene glycol.
 12. A process of claim 9 whereinthe cyclosporin is amorphous cyclosporin A or amorphous cyclosporin G.13. A capsule containing a formulation of claim
 4. 14. A soft gelcapsule of claim
 13. 15. A drinkable solution comprising a formulationof claim
 4. 16. A capsule containing a formulation of claim
 5. 17. Asoft gel capsule of claim
 16. 18. A drinkable solution comprising aformulation of claim
 5. 19. A method of administering cyclosporin to aperson in need thereof, which comprises administering to said person aformulation of claim 4.